Farnesoid X receptor (FXR) is a member of the nuclear receptor family, which is mainly expressed in the intestinal system such as liver, small intestine and other, and involved in links such as bile acid metabolism and cholesterol metabolism. Bile acids have a variety of physiological functions, and play an important role in processes such as fat absorption, transport, distribution and dynamic balance of cholesterol. The farnesoid X receptor acts as a receptor for bile acids such as chenodeoxycholic acid and maintains the in vivo balance of bile acids by regulating the gene expression involved in bile acid metabolism. In addition, the farnesoid X receptor also plays an important role in the in vivo dynamic balance of glucose and insulin resistance. Thus, farnesoid X receptor agonists are expected to be used in the development of drugs for the treatment of nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, gallstones, primary biliary cirrhosis, cirrhosis, liver fibrosis, diabetes, hypercholesterolemia, atherosclerosis, obesity, hypertriglyceridemia, etc.
Deoxycholic acid and its derivatives are a class of agonists of farnesoid X receptors. A series of chenodeoxycholic acid derivatives are disclosed in patents WO2010059859 and WO2005082925, wherein the compound obeticholic acid is a selective farnesoid X receptor agonist, which chemical name is 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid, which can be used in the treatment of non-alcoholic steatohepatitis and nonalcoholic fatty liver-related diseases. At present, obeticholic acid is in phase III clinical study.
Although obeticholic acid has a better clinical effect in improving liver inflammation and fibrosis levels, and has effects such as weight loss and increasing insulin sensitivity, etc, other side effects are also found, such as itching and the raise of low density lipoprotein level. Therefore, the search for farnesoid X receptor agonists selective as well as of high activity and safety is very challenging.
Accordingly, there remains a need in the art for the development of compounds of good activation effect for farnesoid X receptors or better pharmacodynamics/pharmacokinetic properties.